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Evaluation of the blood-brain barrier based on the functional analysis of transporters using newly developed techniques.

使用新开发的技术基于转运蛋白的功能分析来评估血脑屏障。

基本信息

批准号：
12557229
负责人：
TAMAI Ikumi
金额：
$ 5.44万
依托单位：
KANAZAWA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

In the present study, we studied membrane transporters equippecd, in the brain capillary endothelial cells that are functional as the blood-brain barrier. Through this study, we found three new transporters that are expressed at the blood-brain barrier.One of those transporters are monocarboxylic acid transporter MGT1, which tworks for uptake and/or efflux organic weak acids such as lactic acid, pyruvic acid and benzoic acid. The second transporter is neutral amino acid transporters LAT1 and LAT2. These two amino acid transporters work for the uptake of amino acids that are relatively hydrdphpbic and large molecules, including leucine, tyrosine and phenylalanine. These are also important for the brain livery of L-DOPA that is effective for perkinsonism. The third transporter is OCTN2that is callsified as the carnitine/organic cation transporter. OCTN2 is a Na^+-dependent carnitine transporter and works for the brain uptake of acetyl-L-carhitirie that is expected to be useful for Aitzhe … More imer's disease. On the other hand, brain efflux transporters that protect brain from the toxic xenobiotics. As the model drugs, H1-antagonist, ebastine and carebasitine and fluoroquinolone, grepafloxacine, was used in the present study. Generally, fluoroquinolonesand H1 antagonists exhibit adverse effects such as epilepsy and sedative effects, while the drugs studied in the present study do not show such adverse effects. We expected that these drugs might not have enough permeability across the blood-brain barrier, resulting in the insufficient delivery to the brain to cause unfavorable adverse effects. Varipus Kinds of studies on the BBB transport of these drugs demonstrated that there are at least two types of brain efflux transporters, including p-glycoproteih and anion exchange transporter, of which molecular identification remains to be succeeded.All of these studies were performed by using various BBB-transport techniques. Especially, newly developed cell line RBEC1 that were derived from rat brain capillary endothelial cells was useful for the success of the present study. Furthermore, we challenged of the coculture of the endothelial cells and astrocytes in order to mimic the in vivo BBB. Although we partly succeeded to prepare the in vitro BBB model, further improvement will be essential for the efficient and complete model for the evaluation of blood-brain barrier transport. Less

在本研究中，我们研究了在脑毛细血管内皮细胞中作为血脑屏障的膜转运蛋白。通过本研究，我们发现了三种新的血脑屏障转运蛋白，其中一种是一元羧酸转运蛋白MGT 1，其作用是摄取和/或外排有机弱酸，如乳酸、乳酸和苯甲酸。第二种转运蛋白是中性氨基酸转运蛋白LAT 1和LAT 2。这两种氨基酸转运蛋白用于摄取相对疏水的大分子氨基酸，包括亮氨酸、酪氨酸和苯丙氨酸。这些对于L-DOPA的大脑涂装也很重要，L-DOPA对帕金森症有效。第三种转运蛋白是OCTN 2，称为肉毒碱/有机阳离子转运蛋白。OCTN 2是一种Na^+依赖性肉毒碱转运蛋白，可用于脑摄取乙酰-L-肉毒碱，预期对Aitzhe有益。 ...更多信息伊默病另一方面，脑外排转运蛋白保护大脑免受有毒外源性物质的伤害。以H1受体拮抗剂依巴斯汀和卡巴拉汀及氟喹诺酮类药物格列帕新为模型药物。一般来说，氟喹诺酮类和H1拮抗剂表现出不良反应，如癫痫和镇静作用，而在本研究中研究的药物没有表现出这样的不良反应。我们预计这些药物可能没有足够的渗透性穿过血脑屏障，导致向大脑的输送不足，从而引起不利的不良反应。对这些药物的血脑屏障转运的各种研究表明，脑外排转运蛋白至少有两种类型，包括β-糖蛋白和阴离子交换转运蛋白，但它们的分子鉴定仍有待成功，所有这些研究都是利用各种血脑屏障转运技术进行的。特别是，新开发的细胞系RBEC 1，来自大鼠脑毛细血管内皮细胞是有用的，本研究的成功。此外，为了模拟体内血脑屏障，我们挑战了内皮细胞和星形胶质细胞的共培养。虽然我们在体外血脑屏障模型的制备上取得了部分成功，但要建立一个有效、完整的血脑屏障转运模型，还需要进一步的改进。少